Network Meta-analysis of Melatonin Receptor Agonists in the Treatment of Primary Sleep Disorders: Efficacy and Safety Profile
Rana Abdulmohsen Alotaibi, Alaa A. Ismail, Maysun A. Aljohani, Noura B. Alhadhood, Omar Mohammed Alzahrani, Abdullah Khalid Alsaleh, Lina A. Alghamdi, Layan N. Alrehily, Maathir M. Aljuhani, Asma M. BanjarAbstract
Background:
Melatonin receptor agonists represent an important class of medications for primary sleep disorders, but their comparative efficacy and safety remain incompletely understood. The study was to conduct a comprehensive network meta-analysis (NMA) comparing the efficacy and safety of melatonin receptor agonists for the treatment of primary sleep disorders.
Methods:
We searched multiple databases from inception to January 2025 for randomised controlled trials (RCTs) evaluating melatonin receptor agonists (ramelteon, tasimelteon, agomelatine and prolonged-release melatonin) in adults with primary sleep disorders. The primary efficacy outcomes were sleep onset latency (SOL), total sleep time (TST) and sleep efficiency. Safety outcomes included adverse events (AEs) and discontinuations. We performed a Bayesian NMA using random-effects models and assessed the certainty of evidence using the CINeMA approach.
Results:
Fifty-nine RCTs (12,437 participants) were included. All melatonin receptor agonists significantly reduced SOL compared to placebo, with mean differences ranging from −14.8 min (95% credible interval [CRL]: −19.2 to −10.4) for ramelteon to −8.2 min (95% CrI: −13.7 to −2.7) for prolonged-release melatonin. For TST, significant improvements compared to placebo were observed for ramelteon, tasimelteon and agomelatine, but not for prolonged-release melatonin. In head-to-head comparisons, no statistically significant differences were observed among melatonin receptor agonists for most efficacy outcomes. Regarding safety, melatonin receptor agonists demonstrated favorable profiles, with no significant increases in AEs compared to placebo for most agents. Treatment rankings based on surface under the cumulative ranking curve values positioned ramelteon as having the most favorable balance of efficacy and safety among melatonin receptor agonists.
Conclusion:
Melatonin receptor agonists are effective for improving SOL in primary sleep disorders, with ramelteon showing the most favourable efficacy-safety profile. While their effects are more modest than those of traditional hypnotics, their favourable safety profiles make them valuable options, particularly for vulnerable populations.